Diabetic foot ulcers are common and may lead to amputation: efforts to improve foot ulcer healing would have an impact on the frequency of lower limb amputation in the USA. One hundred and fifty patients with diabetes presenting with a new (first or recurrent) neuropathic foot ulcer to either UK or USA diabetic foot centers will be .assessed to examine the effects and the potential mechanisms by which emotional distress influences the healing of chronic wounds. Both generalized distress, (perceived stress, anxiety and depression) and the foot ulcer-specific emotional responses (fear of consequences;hostility towards practitioners and interpersonal emotional burden) will be measured, and the relationship of each type of distress to the pathways involved in foot ulcer healing will be assessed. Two hypothesized pathways by which distress may affect wound healing will be examined: the physiological stress response (altered hormonal regulation of the inflammatory response) and the behavioral pathway (non-adherence to use of offloading modalities)The levels of circulating cortisol will be measured and histological (degree of inflammation and extracelullar matrix disposition) and immunohistochemical analyses of wound biopsies (the type and quantity of inflammatory cells;distribution of growth factors, cytokines and proteases) will be performed at baseline and at the six-week visit. Adherence to the foot ulcer offloading treatment (removable cast walker) will be assessed with a computerized accelerometer. The primary clinical endpoint will be defined as the percentage reduction in the wound size at the six- week visit compared to that at study entry. The results of this study will improve our understanding of mechanisms that might impair healing and will indicate potential targets for future clinical and psychological- behavioral interventions in order to accelerate the healing of diabetic foot ulcers.